Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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High-Dose Rifampicin for 3 Months after Culture Conversion for Drug-Susceptible Pulmonary Tuberculosis

  • Nakwon Kwak (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital) ;
  • Joong-Yub Kim (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital) ;
  • Hyung-Jun Kim (Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Byoung-Soo Kwon (Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Jae Ho Lee (Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Jeongha Mok (Department of Internal Medicine, Pusan National University Hospital, Pusan National University School of Medicine) ;
  • Yong-Soo Kwon (Department of Internal Medicine, Chonnam National University Hospital) ;
  • Young Ae Kang (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine) ;
  • Youngmok Park (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine) ;
  • Ji Yeon Lee (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Medical Center) ;
  • Doosoo Jeon (Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine) ;
  • Jung-Kyu Lee (Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Jeong Seong Yang (Research and Development Center, The Korean Institute of Tuberculosis) ;
  • Jake Whang (Research and Development Center, The Korean Institute of Tuberculosis) ;
  • Kyung Jong Kim (Research and Development Center, The Korean Institute of Tuberculosis) ;
  • Young Ran Kim (Clinical Research Section, International Tuberculosis Research Center) ;
  • Minkyoung Cheon (Medical Research Collaborating Center, Seoul National University Hospital) ;
  • Jiwon Park (Medical Research Collaborating Center, Seoul National University Hospital) ;
  • Seokyung Hahn (Medical Research Collaborating Center, Seoul National University Hospital) ;
  • Jae-Joon Yim (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital)
  • Received : 2024.07.12
  • Accepted : 2024.09.25
  • Published : 2025.01.31
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Abstract

Background: This study aimed to determine whether a shorter high-dose rifampicin regimen is non-inferior to the standard 6-month tuberculosis regimen. Methods: This multicenter, randomized, open-label, non-inferiority trial enrolled participants with respiratory specimen positivity by Xpert MTB/RIF assay or Mycobacterium tuberculosis culture without rifampicin-resistance. Participants were randomized at 1:1 to the investigational or control group. The investigational group received high-dose rifampicin (30 mg/kg/day), isoniazid, and pyrazinamide until culture conversion, followed by high-dose rifampicin and isoniazid for 12 weeks. The control group received the standard 6-month regimen. The primary outcome was the rate of unfavorable outcomes at 18 months post-randomization. The non-inferiority margin was set at <6% difference in unfavorable outcomes rates. The study is registered with ClinicalTrials.gov (NCT04485156) Results: Between 4 November 2020 and 3 January 2022, 76 participants were enrolled. Of these, 58 were included in the modified intention-to-treat analysis. Unfavorable outcomes occurred in 10 (31.3%) of 32 in the control group and 10 (38.5%) of 26 in the investigational group. The difference was 7.2% (95% confidence interval, ∞ to 31.9%), failing to prove non-inferiority. Serious adverse events and grade 3 or higher adverse events did not differ between the groups. Conclusion: The shorter high-dose rifampicin regimen failed to demonstrate non-inferiority but had an acceptable safety profile.

Keywords

Acknowledgement

Rifampicin (Rifampin®) was donated by Korea Yuhan Corporation. We thank members of the Data and Safety Monitoring Board (Dr. Jinsoo Min, Dr. Young Soon Yoon, and Prof. Eun Jin Jang).

References

  1. World Health Organization. Global Tuberculosis Report 2023 [Internet]. Geneva: WHO; 2023 [cited 2024 Oct 18]. Available from: https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2023.
  2. Korea Disease Control and Prevention Agency. Annual report on the notified tuberculosis in Korea [Internet]. Cheongju: Korea Disease Control and Prevention Agency; 2023 [cited 2024 Oct 18]. Available from: https://tbzero.kdca.go.kr/tbzero/content/getTbStats.do.
  3. Fox W, Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946-1986, with relevant subsequent publications. Int J Tuberc Lung Dis 1999;3(10 Suppl 2):S231-79.
  4. World Health Organization. WHO consolidated guidelines on tuberculosis. Module 4: treatment-drug-suscep-tible tuberculosis treatment. Geneva: WHO; 2022.
  5. Birch S, Govender V, Fried J, Eyles J, Daries V, Moshabela M, et al. Does treatment collection and observation each day keep the patient away?: an analysis of the determinants of adherence among patients with Tuberculosis in South Africa. Health Policy Plan 2016;31:454-61. https://doi.org/10.1093/heapol/czv084
  6. Dorman SE, Nahid P, Kurbatova EV, Phillips PP, Bryant K, Dooley KE, et al. Four-month rifapentine regimens with or without moxifloxacin for tuberculosis. N Engl J Med 2021;384:1705-18. https://doi.org/10.1056/NEJMoa2033400
  7. Paton NI, Cousins C, Suresh C, Burhan E, Chew KL, Dalay VB, et al. Treatment strategy for rifampin-susceptible tuberculosis. N Engl J Med 2023;388:873-87. https://doi.org/10.1056/NEJMoa2212537
  8. Louie JK, Agraz-Lara R, Velasquez GE, Phillips A, Szumowski JD. Experience with four-month rifapentine and moxifloxacin-based tuberculosis treatment in San Francisco. Open Forum Infect Dis 2024;11:ofae178. https://doi.org/10.1093/ofid/ofae178
  9. Boeree MJ, Diacon AH, Dawson R, Narunsky K, du Bois J, Venter A, et al. A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis. Am J Respir Crit Care Med 2015;191:1058-65. https://doi.org/10.1164/rccm.201407-1264OC
  10. van Ingen J, Aarnoutse RE, Donald PR, Diacon AH, Dawson R, Plemper van Balen G, et al. Why do we use 600 mg of rifampicin in tuberculosis treatment? Clin Infect Dis 2011;52:e194-9. https://doi.org/10.1093/cid/cir184
  11. Velasquez GE, Brooks MB, Coit JM, Pertinez H, Vargas Vasquez D, Sanchez Garavito E, et al. Efficacy and safety of high-dose rifampin in pulmonary tuberculosis. a randomized controlled trial. Am J Respir Crit Care Med 2018;198:657-66. https://doi.org/10.1164/rccm.201712-2524OC
  12. Svensson EM, Svensson RJ, Te Brake LH, Boeree MJ, Heinrich N, Konsten S, et al. The potential for treatment shortening with higher rifampicin doses: relating drug exposure to treatment response in patients with pulmonary tuberculosis. Clin Infect Dis 2018;67:34-41. https://doi.org/10.1093/cid/ciy026
  13. Kwak N, Jeon D, Park Y, Kang YA, Kim KJ, Kim YR, et al. Treatment shortening of drug-sensitive pulmonary tuberculosis using high-dose rifampicin for 3 months after culture conversion (Hi-DoRi-3): a study protocol for an open-label randomized clinical trial. Trials 2022;23:666. https://doi.org/10.1186/s13063-022-06631-z
  14. World Health Organization. Guidelines for treatment of drug-susceptible tuberculosis and patient care. Geneva: WHO; 2017.
  15. Korea Disease Control and Prevention Agency. Korean guidelines for tuberculosis. 4th ed. Cheongju: Korea Disease Control and Prevention Agency; 2020.
  16. World Health Organization. Definitions and reporting framework for tuberculosis–2013 revision: updated December 2014 and January 2020. Geneva: WHO; 2013.
  17. National Institutes of Health. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [Internet]. Bethesda: NIH; 2017 [cited 2024 Oct 18]. Available from: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf#search=%22CTCAE%22
  18. Lee JK, Lee JY, Kim DK, Yoon HI, Jeong I, Heo EY, et al. Substitution of ethambutol with linezolid during the intensive phase of treatment of pulmonary tuberculosis: a prospective, multicentre, randomised, open-label, phase 2 trial. Lancet Infect Dis 2019;19:46-55. https://doi.org/10.1016/S1473-3099(18)30480-8
  19. Combs DL, O'Brien RJ, Geiter LJ. USPHS Tuberculosis Short-Course Chemotherapy Trial 21: effectiveness, toxicity, and acceptability. The report of final results. Ann Intern Med 1990;112:397-406.
  20. Kwak N, Hwang SS, Yim JJ. Effect of COVID-19 on tuberculosis notification, South Korea. Emerg Infect Dis 2020;26:2506-8. https://doi.org/10.3201/eid2610.202782
  21. Witkowska AB, Wolczynska A, Lis-Cieplak A, Stolarczyk EU. Development and validation of LC-MS/MS method for the determination of 1-methyl-4-nitrosopiperazine(MNP) in multicomponent products with rifampicin: analytical challenges and degradation studies. Molecules 2023;28:7405. https://doi.org/10.3390/molecules28217405
  22. Fox W, Nunn AJ. The cost of antituberculous drug regimens. Am Rev Respir Dis 1979;120:503-9.
  23. Merle CS, Fielding K, Sow OB, Gninafon M, Lo MB, Mthiyane T, et al. A four-month gatifloxacin-containing regimen for treating tuberculosis. N Engl J Med 2014;371:1588-98. https://doi.org/10.1056/NEJMoa1315817
  24. Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, et al. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med 2014;371:1577-87. https://doi.org/10.1056/NEJMoa1407426
  25. de Steenwinkel JE, Aarnoutse RE, de Knegt GJ, ten Kate MT, Teulen M, Verbrugh HA, et al. Optimization of the rifampin dosage to improve the therapeutic efficacy in tuberculosis treatment using a murine model. Am J Respir Crit Care Med 2013;187:1127-34. https://doi.org/10.1164/rccm.201207-1210OC
  26. Liu Y, Pertinez H, Ortega-Muro F, Alameda-Martin L, Harrison T, Davies G, et al. Optimal doses of rifampicin in the standard drug regimen to shorten tuberculosis treatment duration and reduce relapse by eradicating persistent bacteria. J Antimicrob Chemother 2018;73:724-31. https://doi.org/10.1093/jac/dkx467
  27. Boeree MJ, Heinrich N, Aarnoutse R, Diacon AH, Dawson R, Rehal S, et al. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis 2017;17:39-49. https://doi.org/10.1016/S1473-3099(16)30274-2
  28. Jindani A, Atwine D, Grint D, Bah B, Adams J, Ticona ER, et al. Four-month high-dose rifampicin regimens for pulmonary tuberculosis. NEJM Evid 2023;2:EVIDoa2300054. https://doi.org/10.1056/EVIDoa2300054
  29. Ruslami R, Fregonese F, Apriani L, Barss L, Bedingfield N, Chiang V, et al. High-dose, short-duration versus standard rifampicin for tuberculosis preventive treatment: a partially blinded, three-arm, non-inferiority, randomised, controlled trial. Lancet Respir Med 2024;12:433-43. https://doi.org/10.1016/S2213-2600(24)00076-6
  30. Lee E, Kim J, Lee JY, Bang JH. Estimation of the number of HIV Infections and time to diagnosis in the Korea. J Korean Med Sci 2020;35:e41. https://doi.org/10.3346/jkms.2020.35.e41